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Information on EC 1.14.11.30 - hypoxia-inducible factor-asparagine dioxygenase
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1.14.11.30 hypoxia-inducible factor-asparagine dioxygenaseIUBMB Comments
Contains iron, and requires ascorbate. Catalyses hydroxylation of an asparagine in the C-terminal transcriptional activation domain of HIF-alpha, the alpha subunit of the transcriptional regulator HIF (hypoxia-inducible factor), which reduces its interaction with the transcriptional coactivator protein p300. The requirement of oxygen for the hydroxylation reaction enables animals to respond to hypoxia.
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Word Map
- 1.14.11.30
-
prolyl
- hydroxylases
-
transactivation
-
oxygen-dependent
- ankyrin
-
normoxia
-
hippel-lindau
-
oxygen-sensing
-
hif-alpha
-
prolyl-hydroxylase
-
fih-mediated
-
2og-dependent
-
hypoxia-sensitive
- dimethyloxalylglycine
-
2-oxoglutarate-dependent
- medicine
- drug development
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Reaction Schemes
Synonyms
hif1an, asparaginyl hydroxylase, factor inhibiting hif-1, factor-inhibiting hif, asparaginyl-hydroxylase, hypoxia-inducible factor 1-alpha inhibitor, hif asparagine hydroxylase, hypoxia-inducible factor asparagine hydroxylase, 
more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
asparaginyl hydroxylase
FIH
hypoxia-inducible factor 1-alpha inhibitor
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2 = hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
-
-
-
-
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SYSTEMATIC NAME
IUBMB Comments
hypoxia-inducible factor-L-asparagine, 2-oxoglutarate:oxygen oxidoreductase (4-hydroxylating)
Contains iron, and requires ascorbate. Catalyses hydroxylation of an asparagine in the C-terminal transcriptional activation domain of HIF-alpha, the alpha subunit of the transcriptional regulator HIF (hypoxia-inducible factor), which reduces its interaction with the transcriptional coactivator protein p300. The requirement of oxygen for the hydroxylation reaction enables animals to respond to hypoxia.
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
DESGLPQLTSYDAEVNAPIQGSRNLLQGEELLRALDQVN + 2-oxoglutarate + O2
DESGLPQLTSYDAEV-(3S)-3-hydroxy-L-asparaginyl-APIQGSRNLLQGEELLRALDQVN + succinate + CO2
-
-
-
?
DESGLPQLTSYDCEVNAPI + 2-oxoglutarate + O2
?
-
hypoxia-inducible factor-1alpha peptide 788-806. 9% of the activity obtained with the 35-amino-acid HIF-1alpha peptide DES35 (DESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRAL)
-
-
?
DESGLPQLTSYDCEVNAPIQGSR + 2-oxoglutarate + O2
?
-
hypoxia-inducible factor-1alpha peptide 788-810. 15% of the activity obtained with the 35-amino-acid HIF-1alpha peptide DES35 (DESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRAL)
-
-
?
DESGLPQLTSYDCEVNAPIQGSRNLLQ + 2-oxoglutarate + O2
?
-
hypoxia-inducible factor-1alpha peptide 788-814. 37% of the activity obtained with the 35-amino-acid HIF-1alpha peptide DES35 (DESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRAL)
-
-
?
DESGLPQLTSYDCEVNAPIQGSRNLLQGEEL + 2-oxoglutarate + O2
?
-
hypoxia-inducible factor-1alpha peptide 788-818. 26% of the activity obtained with the 35-amino-acid HIF-1alpha peptide DES35 (DESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRAL)
-
-
?
DESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRAL + 2-oxoglutarate + O2
?
-
hypoxia-inducible factor-1alpha peptide 788-822
-
-
?
ESYLLPELTRYDCEVNVPVLGSSTLLQGGDLLRAL + 2-oxoglutarate + O2
?
-
hypoxia-inducible factor-2alpha peptide 832-857. 7% of the activity obtained with the 35-amino-acid HIF-1alpha peptide DES35 (DESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRAL)
-
-
?
hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
hypoxia-inducible factor-L-asparagine peptide + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine peptide + succinate + CO2
-
39-residue peptide corresponding to HIF-1alpha788-826 mutant C800A
hydroxylation at Asn803
-
?
hypoxia-inducible factor1alpha C-terminal oxygen dependent degradation domain-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor1alpha C-terminal oxygen dependent degradation domain-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
-
?
hypoxia-inducible factor1alpha N-terminal oxygen dependent degradation domain-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor1alpha N-terminal oxygen dependent degradation domain-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
-
?
hypoxia-inducible factor2alpha C-terminal oxygen dependent degradation domain-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor2alpha C-terminal oxygen dependent degradation domain-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
-
?
hypoxia-inducible factor2alpha N-terminal oxygen dependent degradation domain-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor2alpha N-terminal oxygen dependent degradation domain-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
-
?
LTRYDCEVNVPVLGSSTLL + O2
?
-
hypoxia-inducible factor-2alpha peptide 839-866. 1% of the activity obtained with the 35-amino-acid HIF-1alpha peptide DES35 (DESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRAL)
-
-
?
LTSYDCEVNAPIQGSRNLL + 2-oxoglutarate + O2
?
-
hypoxia-inducible factor-1alpha peptide 795-813. 4% of the activity obtained with the 35-amino-acid HIF-1alpha peptide DES35 (DESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRAL)
-
-
?
rabankyrin-5 + 2-oxoglutarate + O2
trihydroxy-rabankyrin-5 + succinate + CO2
-
hydroxylation at N316, N485 and N649
-
-
?
additional information
?
-
-
the subtrate contains a C-terminal and a N-terminal oxygen-dependent degradation domain, as well as a C-terminal transactivation domain
-
-
?
hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
-
-
-
-
?
hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
-
activity of the hypoxia-inducible factor (HIF) complex is controlled by oxygen-dependent hydroxylation of prolyl and asparaginyl residues. Hydroxylation of specific prolyl residues by 2-oxoglutarate-dependent oxygenases mediates ubiquitinylation and proteasomal destruction of HIF-alpha. Hydroxylation of an asparagine residue (ASn803) in the C-terminal transactivation domain of HIF-alpha abrogates interaction with p300, preventing transcriptional activation
-
-
?
hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
-
the activity of hypoxia-inducible transcription factor HIF, an alphabeta heterodimer that has an essential role in adaptation to low oxygen availability, is regulated by two oxygen-dependent hydroxylation events. Hydroxylation of specific proline residues by HIF prolyl 4-hydroxylases targets the HIF-alpha subunit for proteasomal destruction, whereas hydroxylation of an asparagine in the C-terminal transactivation domain prevents its interaction with the transcriptional coactivator p300
-
-
?
hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
-
the enzyme requires particularly long peptide substrates, so that omission of only a few residues from the N or C terminus of a 35-residue HIF-1alpha sequence markedly reduces its substrate activity. Hydroxylation of two HIF-2alpha peptides is far less efficient than that of the corresponding HIF-1alpha peptides
-
-
?
hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
-
the oxygen in the alcohol of the hydroxyasparagine residue is directly derived from dioxygen
-
-
?
hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
-
FIH hydroxylates Asn803 of HIF-1alpha
-
-
?
hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
-
FIH hydroxylates at the asparaginyl residue in the FIH transcriptional activation domain C-TAD
-
-
?
hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
-
HIF-1alpha
-
-
?
hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
-
HIF1alpha substrate domain structure, overview. Usage of recombinantly expressed HIFalpha proteins spanning the CODDD region, His6-GB1-TEV-HIF1alpha-(498-603) or His6-GB1-TEV-HIF2alpha-(467-575). The enzyme hydroxylates Asn803 of HIF1alpha and Asn847 of HIF2alpha
-
-
?
hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
hydroxylation at Asn803
-
-
?
PSDLACRLLGQSMDESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRALDQVN + 2-oxoglutarate + O2
?
-
hypoxia-inducible factor-1alpha peptide 775-826. 120% of the activity obtained with the 35-amino-acid HIF-1alpha peptide DES35 (DESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRAL)
-
-
?
PSDLACRLLGQSMDESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRALDQVN + 2-oxoglutarate + O2
?
-
hypoxia-inducible factor-1alpha peptide 775-826. Mutation of Asn803 in GST-HIF-1alpha-(775826) to alanine, glutamine or glutamate abolishes activity, while an Asp803 mutant still supports some 2-oxoglutarate turnover, at a maximum of 7% of the analogous Asn-803 substrate
-
-
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
-
-
-
-
?
hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
-
activity of the hypoxia-inducible factor (HIF) complex is controlled by oxygen-dependent hydroxylation of prolyl and asparaginyl residues. Hydroxylation of specific prolyl residues by 2-oxoglutarate-dependent oxygenases mediates ubiquitinylation and proteasomal destruction of HIF-alpha. Hydroxylation of an asparagine residue (ASn803) in the C-terminal transactivation domain of HIF-alpha abrogates interaction with p300, preventing transcriptional activation
-
-
?
hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
-
the activity of hypoxia-inducible transcription factor HIF, an alphabeta heterodimer that has an essential role in adaptation to low oxygen availability, is regulated by two oxygen-dependent hydroxylation events. Hydroxylation of specific proline residues by HIF prolyl 4-hydroxylases targets the HIF-alpha subunit for proteasomal destruction, whereas hydroxylation of an asparagine in the C-terminal transactivation domain prevents its interaction with the transcriptional coactivator p300
-
-
?
hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
-
FIH hydroxylates Asn803 of HIF-1alpha
-
-
?
hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
-
FIH hydroxylates at the asparaginyl residue in the FIH transcriptional activation domain C-TAD
-
-
?
hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
-
HIF-1alpha
-
-
?
hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
hydroxylation at Asn803
-
-
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Fe2+
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid
-
i.e. JNJ-42041935, 2-oxoglutarate analogue
-
H2O2
-
peroxide rapidly inhibits hydroxlation of diverse FIH substrates and inhibits FIH in a range of cell types. Preferential inhibition of N803-hydroxylation compared with P402/P564 hydroxylation by PHDs, EC 1.14.11.29. Cysteine 800 in HIF-1alpha does not regulate N803 or N847 hydroxylation. FIH activity is not restored by exogenous Fe2+
N-(methoxyoxoacetyl)-glycine methyl ester
-
a pan-hydroxylase inhibitor, in vitro and in vivo inhibition
additional information
-
the Ki-value for 3-hydroxypyridine-2-carbonylglycine and N-((3-hydroxy-6-chloroquinolin-2-yl)carbonyl)glycine are above 0.3 mM
-
additional information
-
construction of peptide inhibitors consist of amino acids identical to those in the HIF1alpha C-terminal oxygen-dependent degradation domain residues 556-575 except for the 564 proline residue: DLDLEALA-L-trans-4-fluoroproline-YIPADDDFQLR, DLDLEALA-L-trans-4-hydroxyproline-YIPADDDFQLR, DLDLEALA-L-piperidine-2-carboxylic acid-YIPADDDFQLR, DLDLEALA-L-3,4-dehydroproline-YIPADDDFQLR, and DLDLEALA-L-4-thioproline-YIPADDDFQLR. All peptide inhibitors show specific inhibition of PHD2, EC 1.14.11.29, and no inhibition of FIH
-
additional information
-
temporal dynamics of hydroxylase inhibition, overview
-
additional information
-
screening of iron chelators pyridines, hydroxypyrones/hydroxypyridinones, and catechols as inhibitors for FIH, analysis of selectivity of the inhibitors for FIH compared to PHD2, EC 1.14.11.29. Ligand binding kinetics and structural analysis, overview. Representative inhibitors bind to the metal center in both FIH as an 2-oxoglutarate mimic
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ferritin heavy chain
i.e. FTH1, directly activates FIH to hydroxylate HIF-1alpha to ensure its normoxic inactivation. In iron-rich conditions, the transcriptional activity of HIF-1alpha is also inhibited due to forceful induction of FTH1
-
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Adenocarcinoma
Expression of erythropoietin and erythropoietin receptor in non-small cell lung carcinomas.
Adenocarcinoma
Interactions between environmental factors and polymorphisms in angiogenesis pathway genes in esophageal adenocarcinoma risk: a case-only study.
Breast Neoplasms
Interactions between RASA2, CADM1, HIF1AN gene polymorphisms and body fatness with breast cancer: a population-based case-control study in China.
Breast Neoplasms
Polymorphisms in microRNA let-7 binding sites of the HIF1AN and CLDN12 genes can predict pathologic complete response to taxane- and platinum-based neoadjuvant chemotherapy in breast cancer.
Breast Neoplasms
Single nucleotide polymorphisms of let-7-related genes increase susceptibility to breast cancer.
Carcinoma
Expression of erythropoietin and erythropoietin receptor in non-small cell lung carcinomas.
Carcinoma, Hepatocellular
A novel HIF1AN substrate KANK3 plays a tumor-suppressive role in hepatocellular carcinoma.
Carcinoma, Squamous Cell
Expression of erythropoietin and erythropoietin receptor in non-small cell lung carcinomas.
Colorectal Neoplasms
Expression and DNA methylation levels of prolyl hydroxylases PHD1, PHD2, PHD3 and asparaginyl hydroxylase FIH in colorectal cancer.
Gastroesophageal Reflux
Interactions between environmental factors and polymorphisms in angiogenesis pathway genes in esophageal adenocarcinoma risk: a case-only study.
Infections
Influenza A virus (H1N1) triggers a hypoxic response by stabilizing hypoxia-inducible factor-1? via inhibition of proteasome.
Kidney Diseases
Genome-Wide Association Study Identifies Novel Loci Associated With Concentrations of Four Plasma Phospholipid Fatty Acids in the De Novo Lipogenesis Pathway: Results from the CHARGE Consortium.
Lymphatic Metastasis
TMEM161B-AS1 suppresses proliferation, invasion and glycolysis by targeting miR-23a-3p/HIF1AN signal axis in oesophageal squamous cell carcinoma.
Myocardial Infarction
Cardioprotective effect of miR-214 in myocardial ischemic postconditioning by down-regulation of hypoxia inducible factor 1, alpha subunit inhibitor.
Neoplasm Metastasis
TMEM161B-AS1 suppresses proliferation, invasion and glycolysis by targeting miR-23a-3p/HIF1AN signal axis in oesophageal squamous cell carcinoma.
Neoplasms
A Noncoding Regulatory RNAs Network Driven by Circ-CDYL Acts Specifically in the Early Stages Hepatocellular Carcinoma.
Neoplasms
Circular RNA CDR1as acts as a sponge of miR-135b-5p to suppress ovarian cancer progression.
Neoplasms
Human placental hypoxia-inducible factor-1alpha expression correlates with clinical outcomes in chronic hypoxia in vivo.
Neoplasms
Human Placental Hypoxia-Inducible Factor-1{alpha} Expression Correlates with Clinical Outcomes in Chronic Hypoxia in Vivo.
Neoplasms
LDH-A influences hypoxia-inducible factor 1? (HIF1 ?) and is critical for growth of HT29 colon carcinoma cells in vivo.
Neoplasms
NECAB3 Promotes Activation of Hypoxia-inducible factor-1 during Normoxia and Enhances Tumourigenicity of Cancer Cells.
Neoplasms
Overexpression of factor inhibiting HIF-1 enhances vessel maturation and tumor growth via platelet-derived growth factor-C.
Neoplasms
The asparaginyl hydroxylase factor-inhibiting HIF is essential for tumor growth through suppression of the p53-p21 axis.
Ovarian Neoplasms
Circular RNA CDR1as acts as a sponge of miR-135b-5p to suppress ovarian cancer progression.
Pre-Eclampsia
[Clinical significance of hypoxia inducible factor-prolyl hydroxylase 1 and factor inhibiting hypoxia inducible factor-1 expression in placentas of women with severe pre-eclampsia]
Prostatic Neoplasms
MicroRNA-135b regulates ER?, AR and HIF1AN and affects breast and prostate cancer cell growth.
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
-
steady-state kinetic analysis and substrate selectivity for hypoxia-inducible factor and 2-oxoglutarate
-
0.025
2-oxoglutarate
-
pH 7.8, 37°C, Km-value is determined using soluble extracts of cells expressing enzyme-FLAGHis
0.07
DESGLPQLTSYDAEVNAPIQGSRNLLQGEELLRALDQVN
mutant enzyme D210E, at pH 7.0 and 37°C
-
0.071
DESGLPQLTSYDAEVNAPIQGSRNLLQGEELLRALDQVN
mutant enzyme D210G, at pH 7.0 and 37°C
-
0.078
DESGLPQLTSYDAEVNAPIQGSRNLLQGEELLRALDQVN
wild type enzyme, at pH 7.0 and 37°C
-
0.09
O2
-
pH 7.8, 37°C. The Km of FIH for O2 is about 40% of its atmospheric concentration, Km-value is determined using soluble extracts of cells expressing enzyme-FLAGHis
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
-
the catalytic center activities obtained for the enzyme purified by two alternative procedures are 85-135 and 70-120 mol/mol/min, respectively
-
0.027
DESGLPQLTSYDAEVNAPIQGSRNLLQGEELLRALDQVN
mutant enzyme D210E, at pH 7.0 and 37°C
-
0.383
DESGLPQLTSYDAEVNAPIQGSRNLLQGEELLRALDQVN
mutant enzyme D210G, at pH 7.0 and 37°C
-
0.55
DESGLPQLTSYDAEVNAPIQGSRNLLQGEELLRALDQVN
wild type enzyme, at pH 7.0 and 37°C
-
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.37
DESGLPQLTSYDAEVNAPIQGSRNLLQGEELLRALDQVN
mutant enzyme D210E, at pH 7.0 and 37°C
-
5.7
DESGLPQLTSYDAEVNAPIQGSRNLLQGEELLRALDQVN
mutant enzyme D210G, at pH 7.0 and 37°C
-
7
DESGLPQLTSYDAEVNAPIQGSRNLLQGEELLRALDQVN
wild type enzyme, at pH 7.0 and 37°C
-
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.01
3,4-dihydroxybenzoate
-
pH 7.8, 37°C, Ki-value is determined using soluble extracts of cells expressing enzyme-FLAGHis
0.1
DESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRAL
-
pH 7.8, 37°C, Ki-value is determined using soluble extracts of cells expressing enzyme-FLAGHis
0.16
ESYLLPELTRYDCEVNVPVLGSSTLLQGGDLLRAL
-
pH 7.8, 37°C, Ki-value is determined using soluble extracts of cells expressing enzyme-FLAGHis
0.002
oxalylglycine
-
pH 7.8, 37°C, Ki-value is determined using soluble extracts of cells expressing enzyme-FLAGHis
0.1
PSDLACRLLGQSMDESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRALDQVN
-
pH 7.8, 37°C, Ki-value is determined using soluble extracts of cells expressing enzyme-FLAGHis
-
0.03
Pyridine-2,4-dicarboxylate
-
pH 7.8, 37°C, Ki-value is determined using soluble extracts of cells expressing enzyme-FLAGHis
0.05
Pyridine-2,5-dicarboxylate
-
pH 7.8, 37°C, Ki-value is determined using soluble extracts of cells expressing enzyme-FLAGHis
additional information
additional information
-
the Ki-value for 3-hydroxypyridine-2-carbonylglycine and N-((3-Hydroxy-6-chloroquinolin-2-yl)carbonyl)glycine are above 0.3 mM
-
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
-
-
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
expresses 50fold higher levels of FIH than other tissues
brenda
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
-
the enzyme belongs to the 2-oxoglutarate- and iron-dependent dioxygenase family of enzymes
malfunction
metabolism
physiological function
additional information
malfunction
-
FIH silencing leads to spacial displacement of the expression pattern of HIF target genes that depend on the C-TAD, such as carbonic anhydrase IX, to more oxygenated areas, whereas overexpression of FIH restricts this pattern to more hypoxic areas. Silencing of gene fih severely reduced in vitro cell proliferation and in vivo tumor growth of LS174 colon adenocarcinoma and A375 melanoma cells. Silencing of fih also significantly increases both the total and phosphorylated forms of the tumor suppressor p53, leading to an increase in its direct target, the cell cycle inhibitor p21. p53-deficient or mutant cells are totally insensitive to FIH expression. FIH activity is essential for tumor growth through the suppression of the p53-p21 axis, the major barrier that prevents cancer progression
malfunction
-
silencing FIH under conditions where prolyl hydroxylases, EC 1.14.11.29/30, are inhibited results in increased HIF-1alpha transcriptional activity, but paradoxically decreases HIF-1alpha stability. Residual activity of FIH in hypoxia
malfunction
-
the lower enzyme expression in tumor is associated with incomplete tumor encapsulation, vascular invasion, and microvascular density
metabolism
-
HIF transcriptional activity is controlled by the asparaginyl hydroxylase factor inhibiting HIF-1. Hypoxia-induced HIF signalling, mathematical modelling of the pathway, temporal dynamics of the HIF response to hypoxia, and molecular interaction map for the HIF network, overview. The hypoxia inducible factor is switched on and promotes adaptation to hypoxia by upregulating genes involved in angiogenesis, erythropoiesis and glycolysis
metabolism
-
hypoxia and oxidant stress can interact functionally as distinct regulators of HIF transcriptional output involving the enzyme. Oxidant stress activates hypoxia pathways through the inactivation of the oxygen-sensing hypoxia-inducible factor prolyl and asparaginyl hydroxylases
metabolism
-
optimal HIF-1alpha transcriptional activity requires sequential inhibition of both prolyl- and asparaginyl-hydroxylases
physiological function
-
there are at least two major steps involved in the hypoxic induction of the HIF proteins: (i) inhibition of oxygen-dependent hydroxylation on Pro residues in the oxygen-dependent degradation domain to prevent interaction of HIF with the von Hippel-Lindau tumor suppressor/ubiquitin ligase complex and thus avoid proteasomal destruction, and (ii) inhibition of oxygen-dependent hydroxylation of Asn in the COOH-terminal transactivation domain to promote interaction with the p300/CBP coactivator and induce transcription
physiological function
-
FIH modulates the profile of hypoxia-inducible factor downstream genes and of hypoxia-inducible factor target genes in a physiological oxygen gradient: the in vitro spheroid model, overview. FIH enhances tumorigenesis and controls in vitro p53 expression. Factor-inhibiting hypoxia-inducible factor monitors the expression of a spectrum of genes that are dictated by the cell's partial oxygen pressure. This action is mediated by the C-TAD, one of two transactivation domains of the hypoxia-inducible factor
physiological function
-
HIF transcriptional activity is controlled by the asparaginyl hydroxylase factor inhibiting HIF-1
physiological function
-
key enzyme in activation of the hypoxia-inducible factor (HIF) pathway, a critical step in the transcriptional response to hypoxia, role of FIH in hydroxylase regulation of HIF-1alpha, overview. The enzyme is involved in the HIF-1alpha signalling network, overview. Asparaginyl hydroxylation confers upon HIF-1alpha resistance to proteosomal degradation, but the removal of the asparaginyl hydroxylation step is necessary for HIF-1alpha activity
physiological function
-
the enzyme inhibits the hypoxia-inducible factor transcription activation through asparagine hydroxylation
physiological function
-
the FIH hydroxylase is a cellular peroxide sensor that modulates HIF transcriptional activity. Cysteine 800 in HIF-1alpha does not regulate N803 or N847 hydroxylation
physiological function
ferritin heavy chain FTH1 directly interacts with FIH. FTH1 facilitates the FIH-mediated Asn803 hydroxylation in hypoxia-inducible factor HIF-1alpha and prevents the recruitment of p300 to HIF-1alpha through the Asn803 hydroxylation. FTH1 represses the transcriptional activity of HIF-1alpha in HCT-116 cells under either normoxic or hypoxic conditions and downregulates the expression of the HIF-1 target genes
physiological function
FIH loss increases oxidative metabolism and also increases glycolytic capacity, this gives rise to an increase in oxygen consumption. The loss of FIH acts to accelerate the cellular metabolic response to hypoxia. FIH suppresses hypoxia-induced mitochondrial reactive oxygen species production and FIH loss accelerates the effects of hypoxic exposure on mitochondria
physiological function
the enzyme controls HIF transcriptional activity in an oxygen-dependent manner
additional information
-
HIF asparaginyl hydroxylase is strikingly more sensitive to peroxide than the HIF prolyl hydroxylases, EC 1.14.11.29. Inhibition of FIH by peroxide persists in hypoxia
additional information
-
modeling of the dynamic regulation of HIF-1alpha transcriptional activity by the hydroxylase. HIF-1alpha stabilisation and transcriptional activity is dependent on oxygen tension
additional information
-
PHD, EC 1.14.11.29, has a higher affinity for oxygen than FIH
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UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). HIF1N_DANRE
344
0
39992
Swiss-Prot
other Location (Reliability: 2)
HIF1N_HUMAN
349
0
40285
Swiss-Prot
other Location (Reliability: 2)
HIF1N_MOUSE
349
0
40241
Swiss-Prot
other Location (Reliability: 2)
A0A6J8D0E4_MYTCO
331
0
38718
TrEMBL
other Location (Reliability: 3)
A0A8B6G2T8_MYTGA
417
0
48845
TrEMBL
other Location (Reliability: 2)
A0A7H1K1G8_MELCN
963
0
106926
TrEMBL
other Location (Reliability: 1)
A0A8B6HCC6_MYTGA
174
0
20149
TrEMBL
other Location (Reliability: 3)
A0A8B6G2R6_MYTGA
134
0
15859
TrEMBL
other Location (Reliability: 2)
A0A8B6G2Q2_MYTGA
324
0
37723
TrEMBL
other Location (Reliability: 4)
A0A812CQG6_SEPPH
227
0
26632
TrEMBL
other Location (Reliability: 1)
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PDB
SCOP
CATH
UNIPROT
ORGANISM
4bio,